6-11 Bridged Oxime Erythromycin Derivatives

ABSTRACT

The present invention discloses compounds of formula I, or pharmaceutically acceptable salts, esters, or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     which exhibit antibacterial properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of antibiotic treatment. The invention also relates to methods of treating a bacterial infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The invention further includes processes by which to make the compounds of the present invention.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/416,609, filed May 3, 2006, which claims the benefit of U.S.application Ser. No. 11/122,251, now abandoned, filed on May 4, 2005 andU.S. Provisional Application No. 60/677,675, filed on May 4, 2005. Theentire teachings of the above applications are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to novel semisynthetic macrolides havingantibacterial activity and useful in the treatment and prevention ofbacterial infections. More particularly, the invention relates to 6-11bicyclic macrolide, ketolide, and anhydrolide derivatives, compositionscontaining such compounds and methods for using the same, as well asprocesses for making such compounds.

BACKGROUND OF THE INVENTION

Macrolide antibiotics play a therapeutically important role,particularly with the emergence of new pathogens. Structural differencesare related to the size of the lactone ring and to the number and nature(neutral or basic) of the sugars. Macrolides are classified according tothe size of the lactone ring (12, 14, 15 or 16 atoms). The macrolideantibiotic family (14-, 15- and 16-membered ring derivatives) shows awide range of characteristics (antibacterial spectrum, side-effects andbioavailability). Among the commonly used macrolides are erythromycin,clarithromycin, and azithromycin. Macrolides possessing a 3-oxo moietyin place of the 3-cladinose sugar are known as ketolides and have shownenhanced activity towards gram-negative bacteria and macrolide resistantgram-positive bacteria. Macrolides possessing a degree of unsaturationbetween carbons 2 and 3 or between carbons 3 and 4 of the erythromycinmacrocycle are known as anhydrolides. The search for macrolide compoundswhich are active against MLS_(B)-resistant strains(MLS_(B)=Macrolides-Lincosamides-type B Streptogramines) has become amajor goal, together with retaining the overall profile of themacrolides in terms of stability, tolerance and pharmacokinetics.

International Application WO 97/42205 of Elliott et al, published Nov.13, 1997, discloses 3-descladinose-2,3-anhydroerythromycin derivativeshaving a cyclic carbamate and cyclic carbazate basic nuclear structure.Further details were also disclosed in J. Med Chem., 41, pp 1651-1659(1998) and J. Med Chem., 41, pp 1660-1670 (1998) by Elliott et al, andby Griesgraber et al, respectively.

U.S. Pat. No. 5,444,051 discloses certain6-O-substituted-3-oxoerythromycin A derivatives. PCT application WO97/10251, published Mar. 20, 1997, discloses intermediates useful forpreparation of 6-O-methyl 3-descladinose erythromycin derivatives. U.S.Pat. No. 5,631,355 discloses certain tricyclic 6-O-methyl 3-oxoerythromycin derivatives. U.S. Pat. No. 5,527,780 discloses certainbicyclic 6-O-methyl-3-oxo erythromycin A derivatives (Agouridas,ROUSSEL) corresponding to EP application 596802, published May 11, 1994.U.S. Pat. Nos. 5,866,549 and 6,075,011, and PCT application WO 00/78773,published Dec. 28, 2000, disclose certain 6-O-substituted erythromycinderivatives. U.S. Pat. No. 6,124,269 and PCT application WO 00/62783,published Oct. 26, 2000, disclose certain 2-halo-6-O-substitutedketolide derivatives. U.S. Pat. No. 6,046,171 and PCT application WO99/21864, published May 6, 1999, disclose certain 6,11-bridgederythromycin derivatives.

PCT Application WO 03/095466 A1, published Nov. 20, 2003 and PCTApplication WO 03/097659 A1, published Nov. 27, 2003 disclose a seriesof bicyclic erythromycin derivatives.

SUMMARY OF THE INVENTION

The present invention provides a novel class of C6-C11 bridged oximeerythromycin derivatives which possess antibacterial activity.

In one aspect of the present invention there are provided novel bridgederythromycin compounds represented by the formulae as illustrated below:

or their racemates, enantiomers, regioisomers, salts, esters or prodrugsthereof, wherein

X and Y are independently selected from the group consisting of:hydrogen, deuterium, halogen, R₁, OR₁, S(O)_(n)R₁, —NR₁C(O)R₂,—NR₁C(O)NR₃R₄, —NR₁S(O)_(n)R₂, —C(O)NR₃R₄, and —NR₃R₄;

Each of R₁ and R₂ is independently selected from the group consistingof: hydrogen, acyl, silane, a substituted or unsubstituted, saturated orunsaturated aliphatic group, a substituted or unsubstituted, saturatedor unsaturated alicyclic group, a substituted or unsubstituted aromaticgroup, a substituted or unsubstituted heteroaromatic group, or asubstituted or unsubstituted heterocyclic group;

Each of R₃ and R₄ is independently selected from the group consistingof: hydrogen, acyl, a substituted or unsubstituted, saturated orunsaturated aliphatic group, a substituted or unsubstituted, saturatedor unsaturated alicyclic group, a substituted or unsubstituted aromaticgroup, a substituted or unsubstituted heteroaromatic group, asubstituted, or unsubstituted heterocyclic group; or can be takentogether with the nitrogen atom to which they are attached to form asubstituted or unsubstituted heterocyclic or heteroaromatic ring;

or X and Y, taken together with the carbon atom to which they areattached, are selected from the group consisting of: CO, C═CHR₁, C═NR₁,C═NC(O)R₁, C═NOR₁, C═NO(CH₂)_(m)R₁, C═NNHR₁, C═NNHCOR₁, C═NNHCONR₁R₂,C═NNHS(O)_(n)R₁, C═N—N═CHR₁, C═N—NO₂, or C═N—ONO;

one of U or V is hydrogen and the other is independently selected fromthe group consisting of: R₁, OR₁, OC(O)R₁, OC(O)NR₃R₄, S(O)_(n)R₁,

or U and V, taken together with the carbon atom to which they areattached, are C═O;

one of J or G is hydrogen and the other is selected from: R₁, OR₁, orNR₃R₄;

or, J and G, taken together with the carbon atom to which they areattached, are selected from: C═O, C═NR₁, C═NOR₁, C═NO(CH₂)_(m)R₁,C═NNHR₁, C═NNHCOR₁, C═NNHCONR₁R₂, C═NNHS(O)_(n)R₁, or C═N—N═CHR₁;

L is selected from the group consisting of: hydrogen, a substituted orunsubstituted, saturated or unsaturated aliphatic group, a substitutedor unsubstituted, saturated or unsaturated alicyclic group, asubstituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group, or a substituted or unsubstitutedheterocyclic group;

M is R₁;

W is NR₃R₄;

Z is hydrogen, alkyl or halogen;

R_(p) is hydrogen, hydroxy protecting group or hydroxy prodrug group;

m is an integer; and

n is 0, 1, or 2.

A is

wherein:

Q′ is N, CH or CF;

X₁ is O, N, NR₁, S, or CR₅;

Y₁ is O, N, NR₁, S, CR₅, or Se;

Z₁ is O, N, NR₁, S, or CR₅;

R₅ is independently selected from hydrogen, acyl, silane, a substitutedor unsubstituted, saturated or unsaturated aliphatic group, asubstituted or unsubstituted, saturated or unsaturated alicyclic group,a substituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group, a substituted or unsubstitutedheterocyclic group, NR₃R₄, OH, NHCOR₁ or NHCONH₂, and is preferably, NH₂or NHR₁.

With the proviso that a compound of Formula I is not selected fromcompound having the following formula where A, Q, and Z as defined belowin the table A.

TABLE A Compound A Q Z 01

NAc H 02

NAc H 03

NH H 04

NAc H

In one preferred embodiment, A is:

wherein X₁, and R₅ is as defined previously.

In another preferred embodiment, A is:

wherein X₁ is O, NH or S, and R₅ is as defined previously.

In yet another embodiment, A is:

wherein X₁ is O, NH or S, and R₅ is as defined previously.

In yet another embodiment, A is:

wherein R₅ is as defined previously.

In yet another embodiment, A is:

In one preferred embodiment, A is selected from the compounds shown inTable B.

TABLE B Number A- 01

02

03

04

05

06

07

08

09

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

One preferred compound of the invention has the formula II:

Where in A, Q, and Z are as defined in Table C:

TABLE C Num- ber A Q Z 01

NAc H 02

NAc F 03

NAc H 04

NAc H 05

NAc H 06

NAc H 07

NAc H 08

NAc F 09

O H 10

NAc H 11

O H 12

NAc H 13

NAc H 14

O H 15

O H 16

NAc H 17

NAc H 18

O H 19

NAc H 20

NAc H 21

NAc F 22

NAc F 23

NAc H 24

O H 25

NAc H 26

NAc H 27

NAc H 28

O H 29

NAc H 30

NAc H 31

NAc H 32

NAc H 33

NAc H 34

NAc H 35

NAc H 36

NAc H 37

NAc H 38

NC(O)OCH₃ H 39

NH H

One preferred compound of the invention has the formula III:

wherein R_(p), U, V, W, X, Y, L, and Z are as defined previously.

Another preferred compound of the invention has the formula IV:

wherein Z and R_(p) are as previously defined.

Yet another preferred compound of the invention has the formula V:

wherein Z and R_(p) are as defined previously.

In another aspect of the invention, there are provided novel 3-acylidebridged erythromycin compounds represented by the Formula VI:

or any racemates, enantiomers, regioisomers, salts, esters, or prodrugsthereof wherein X, Y, L, W, and R_(p) are as defined previously;

B is independently selected from hydrogen, acyl, silane, a substitutedor unsubstituted, saturated or unsaturated aliphatic group, asubstituted or unsubstituted, saturated or unsaturated alicyclic group,a substituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group, or a substituted or unsubstitutedheterocyclic group.

One preferred compound of Formula VI has the formula VII:

wherein R_(p) is as previously defined.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

An “aliphatic group” is non-aromatic moiety that may contain anycombination of carbon atoms, hydrogen atoms, halogen atoms, oxygen,nitrogen or other atoms, and optionally contain one or more units ofunsaturation, e.g., double and/or triple bonds. An aliphatic group maybe straight chained, branched or cyclic and preferably contains betweenabout 1 and about 24 carbon atoms, more typically between about 1 andabout 12 carbon atoms. In addition to aliphatic hydrocarbon groups,aliphatic groups include, for example, polyalkoxyalkyls, such aspolyalkylene glycols, polyamines, and polyimines, for example. Suchaliphatic groups may be further substituted.

The terms “C₁-C₃ alkyl,” “C₁-C₆ alkyl,” or “C₁-C₁₂ alkyl,” as usedherein, refer to saturated, straight- or branched-chain hydrocarbonradicals containing between one and three, one and twelve, or one andsix carbon atoms, respectively. Examples of C₁-C₃ alkyl radicals includemethyl, ethyl, propyl and isopropyl radicals; examples of C₁-C₆ alkylradicals include, but are not limited to, methyl, ethyl, propyl, propyl,butyl, pentyl, and hexyl radicals; and examples of C₁-C₁₂ alkyl radicalsinclude, but are not limited to, ethyl, propyl, propyl, hexyl, heptyl,octyl, nonyl, decyl, undecyl, dodecyl radicals and the like.

The term “substituted alkyl,” as used herein, refers to an alkyl, suchas a C₁-C₁₂ alkyl or C₁-C₆ alkyl group, substituted by one, two, threeor more aliphatic or aromatic substituents.

Suitable aliphatic or aromatic substituents include, but are not limitedto, —F, —Cl, —Br, —I, —OH, protected hydroxy, aliphatic ethers, aromaticethers, oxo, —NO₂, —CN, —C₁-C₁₂-alkyl optionally substituted withhalogen (such as perhaloalkyls), C₂-C₁₂-alkenyl optionally substitutedwith halogen, —C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂,protected amino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl,—NH—C₂-C₁₂-alkynyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkynyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkynyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkynyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl, —CO₂—C₁-C₁₂-alkyl,—CO₂—C₂-C₁₂-alkenyl, —CO₂—C₂-C₁₂-alkynyl, —CO₂—C₃-C₁₂-cycloalkyl,—CO₂-aryl, —CO₂-heteroaryl, —CO₂-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkynyl, —OCO₂—C₃-C₁₂-cycloalkyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂,—OCONH—C₁-C₁₂-alkyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkynyl,—OCONH—C₃-C₁₂-cycloalkyl, —OCONH— aryl, —OCONH-heteroaryl,—OCONH-heterocycloalkyl, —NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₂-C₁₂-alkynyl, —NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl,—NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl,—NHCO₂— aryl, —NHCO₂— heteroaryl, —NHCO₂— heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkynyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkynyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkynyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH— aryl, —SO₂NH— heteroaryl, —SO₂NH— heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkylsand the like can be further substituted.

The terms “C₂-C₁₂ alkenyl” or “C₂-C₆ alkenyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbondouble bond by the removal of a single hydrogen atom. Alkenyl groupsinclude, but are not limited to, for example, ethenyl, propenyl,butenyl, 1-methyl-2-buten-1-yl, alkadienes and the like.

The term “substituted alkenyl,” as used herein, refers to a “C₂-C₁₂alkenyl” or “C₂-C₆ alkenyl” group as previously defined, substituted byone, two, three or more aliphatic substituents.

The terms “C₂-C₁₂ alkynyl” or “C₂-C₆ alkynyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbontriple bond by the removal of a single hydrogen atom. Representativealkynyl groups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, and the like.

The term “substituted alkynyl,” as used herein, refers to a “C₂-C₁₂alkynyl” or “C₂-C₆ alkynyl” group as previously defined, substituted byone, two, three or more aliphatic substituents.

The term “C₁-C₆ alkoxy,” as used herein, refers to a C₁-C₆ alkyl group,as previously defined, attached to the parent molecular moiety throughan oxygen atom. Examples of C₁-C₆-alkoxy include, but are not limitedto, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy, n-pentoxy, neopentoxy and n-hexoxy.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The terms “aryl” or “aromatic,” as used herein, refer to a mono- orbicyclic carbocyclic ring system having one or two aromatic ringsincluding, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, idenyl and the like.

The terms “substituted aryl” or “substituted aromatic,” as used herein,refer to an aryl group, as previously defined, substituted by one, two,three or more aromatic substituents.

The term “arylalkyl,” as used herein, refers to an aryl group attachedto the parent compound via a C₁-C₃ alkyl or C₁-C₆ alkyl residue.Examples include, but are not limited to, benzyl, phenethyl and thelike.

The term “substituted arylalkyl,” as used herein, refers to an arylalkylgroup, as previously defined, substituted by one, two, three or morearomatic substituents.

The terms “heteroaryl” or “heteroaromatic,” as used herein, refers to amono-, bi-, or tri-cyclic aromatic radical or ring having from five toten ring atoms of which at least one ring atom is selected from S, O andN; zero, one, two, three or more ring atoms are additional heteroatomsindependently selected from S, O and N; and the remaining ring atoms arecarbon, wherein any N or S contained within the ring may be optionallyoxidized. Heteroaryl includes, but is not limited to, pyridinyl,pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl,tetrazolyl and the like. The heteroaromatic ring may be bonded to thechemical structure through a carbon or hetero atom.

The terms “substituted heteroaryl” or “substituted heteroaromatic,” asused herein, refer to a heteroaryl group as previously defined,substituted by one, two, three or four aromatic substituents.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or bicyclic saturated carbocyclic ring compound by theremoval of a single hydrogen atom. Examples include, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl,and bicyclo[2.2.2]octyl.

The term “substituted alicyclic” group as previously defined,substituted by one, two, three or more aliphatic substituents.

The terms “heterocyclic” as used herein, refers to a non-aromatic 5-, 6-or 7-membered ring or a bi- or tri-cyclic group fused system, where (i)each ring contains between one and three heteroatoms independentlyselected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds,(iii) the nitrogen and sulfur heteroatoms may optionally be oxidized,(iv) the nitrogen heteroatom may optionally be quaternized, (iv) any ofthe above rings may be fused to a benzene ring, and (v) the remainingring atoms are carbon atoms which may be optionally oxo-substituted.Representative heterocycloalkyl groups include, but are not limited to,[1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl,pyridazinonyl, tetrahydrofuryl, and the like.

The term “substituted heterocyclic,” as used herein, refers to aheterocyclic group, as previously defined, substituted by one, two,three or more aliphatic substituents.

The term “heteroarylalkyl,” as used herein, refers to a heteroaryl groupattached to the parent compound via a C₁-C₃ alkyl or C₁-C₆ alkylresidue. Examples include, but are not limited to, pyridinylmethyl,pyrimidinylethyl and the like.

The term “substituted heteroarylalkyl,” as used herein, refers to aheteroarylalkyl group, as previously defined, substituted by independentreplacement of one, two, or three or more aromatic substituents.

The term “C₁-C₃-alkylamino,” as used herein, refers to one or twoC₁-C₃-alkyl groups, as previously defined, attached to the parentmolecular moiety through a nitrogen atom. Examples of C₁-C₃-alkylaminoinclude, but are not limited to, methylamino, dimethylamino, ethylamino,diethylamino, and propylamino.

The term “alkylamino” refers to a group having the structure —NH(C₁-C₁₂alkyl) where C₁-C₁₂ alkyl is as previously defined.

The term “dialkylamino” refers to a group having the structure —N(C₁-C₁₂alkyl) (C₁-C₁₂ alkyl), where C₁-C₁₂ alkyl is as previously defined.Examples of dialkylamino are, but not limited to, dimethylamino,diethylamino, methylethylamino, piperidino, and the like.

The term “alkoxycarbonyl” represents an ester group, i.e., an alkoxygroup, attached to the parent molecular moiety through a carbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl, and the like.

The term “carboxaldehyde,” as used herein, refers to a group of formula—CHO.

The term “carboxy,” as used herein, refers to a group of formula —COOH.

The term “carboxamide,” as used herein, refers to a group of formula—C(O)NH(C₁-C₁₂ alkyl) or —C(O)N(C₁-C₁₂ alkyl) (C₁-C₁₂ alkyl), —C(O)NH₂,—NHC(O)(C₁-C₁₂ alkyl), —N(C₁-C₁₂ alkyl)C(O)(C₁-C₁₂ alkyl) and the like.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theart are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl(trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxyl protecting groups for the present invention areacetyl (Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl(TMS or —Si(CH₃)₃).

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy prodrug group”, as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al, Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protogenic organic solvent” or “protic solvent,” as usedherein, refers to a solvent that tends to provide protons, such as analcohol, for example, methanol, ethanol, propanol, isopropanol, butanol,t-butanol, water and the like. Such solvents are well known to thoseskilled in the art, and it will be obvious to those skilled in the artthat individual solvents or mixtures thereof may be preferred forspecific compounds and reaction conditions, depending upon such factorsas the solubility of reagents, reactivity of reagents and preferredtemperature ranges, for example. Further discussions of protogenicsolvents may be found in organic chemistry textbooks or in specializedmonographs, for example: Organic Solvents Physical Properties andMethods of Purification, 4th ed., edited by John A. Riddick et al., Vol.II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)— or (S)—, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. The configuration ofany carbon-carbon double bond appearing herein is selected forconvenience only and is not intended to designate a particularconfiguration unless the text so states; thus a carbon-carbon doublebond or carbon-heteroatom double bond depicted arbitrarily herein astrans may be cis, trans, or a mixture of the two in any proportion.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid or inorganic acid. Examples of pharmaceuticallyacceptable nontoxic acid addition salts include, but are not limited to,salts of an amino group formed with inorganic acids such as hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloricacid or with organic acids such as acetic acid, maleic acid, tartaricacid, citric acid, succinic acid lactobionic acid or malonic acid or byusing other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include, but are not limited to,adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of the invention. Various forms of prodrugs are known in theart, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); and Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

This invention also encompasses pharmaceutical compositions containing,and methods of treating bacterial infections through administering,pharmaceutically acceptable prodrugs of compounds of the invention. Forexample, compounds of the invention having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of the invention. The amino acidresidues include but are not limited to the 20 naturally occurring aminoacids commonly designated by three letter symbols and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

As used herein, unless otherwise indicated, the term “bacterialinfection(s)” or “protozoa infections”; includes, but is not limited to,bacterial infections and protozoa infections that occur in mammals, fishand birds as well as disorders related to bacterial infections andprotozoa infections that may be treated or prevented by administeringantibiotics such as the compounds of the present invention. Suchbacterial infections and protozoa infections and disorders related tosuch infections include, but are not limited to, the following:pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, cysticfibrosis (CF) and mastoiditis related to infection by Streptococcuspneumoniae, Haemophilus influenzae, Moraxella catarrhalis,Staphylococcus aureus, Peptostreptococcus spp. or Pseudomonas spp.;pharynigitis, rheumatic fever, and glomerulonephritis related toinfection by Streptococcus pyogenes, Groups C and G streptococci,Clostridium diptheriae, or Actinobacillus haemolyticum; respiratorytract infections related to infection by Mycoplasma pneumoniae,Legionella pneumophila, Streptococcus pneumoniae, Haemophilusinfluenzae, or Chlamydia pneumoniae; uncomplicated skin and soft tissueinfections, abscesses and osteomyelitis, and puerperal fever related toinfection by Staphylococcus aureus, coagulase-positive staphylococci(i.e., S. epidermidis, S. hemolyticus, etc.), S. pyogenes, S.agalactiae, Streptococcal groups C-F (minute-colony streptococci),viridans streptococci, Corynebacterium spp., Clostridium spp., orBartonella henselae; uncomplicated acute urinary tract infectionsrelated to infection by S. saprophyticus or Enterococcus spp.;urethritis and cervicitis; and sexually transmitted diseases related toinfection by Chlamydia trachomatis, Haemophilus ducreyi, Treponemapallidum, Ureaplasma urealyticum, or Nesseria gonorrheae; toxin diseasesrelated to infection by S. aureus (food poisoning and Toxic shocksyndrome), or Groups A, S, and C streptococci; ulcers related toinfection by Helicobacter pylori; systemic febrile syndromes related toinfection by Borrelia recurrentis; Lyme disease related to infection byBorrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitisrelated to infection by C. trachomatis, N. gonorrhoeae, S. aureus, S.pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminatedMycobacterium avium complex (MAC) disease related to infection byMycobacterium avium, or Mycobacterium intracellulare; tuberculosisdisease related to infection by Mycobacterium tuberculosis;gastroenteritis related to infection by Campylobacter jejuni; intestinalprotozoa related to infection by Cryptosporidium spp. odontogenicinfection related to infection by viridans streptococci; persistentcough related to infection by Bordetella pertussis; gas gangrene relatedto infection by Clostridium perfringens or Bacteroides spp.; Skininfection by S. aureus, Propionibacterium acne; atherosclerosis relatedto infection by Helicobacter pylori or Chlamydia pneumoniae; or thelike.

Bacterial infections and protozoa infections and disorders related tosuch infections that may be treated or prevented in animals include, butare not limited to, the following: bovine respiratory disease related toinfection by P. haemolytica., P. multocida, Mycoplasma bovis, orBordetella spp.; cow enteric disease related to infection by E. coli orprotozoa (i.e., coccidia, cryptosporidia, etc.), dairy cow mastitisrelated to infection by S. aureus, S. uberis, S. agalactiae, S.dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.;swine respiratory disease related to infection by A. pleuropneumoniae.,P. multocida, or Mycoplasma spp.; swine enteric disease related toinfection by E. coli, Lawsonia intracellularis, Salmonella spp., orSerpulina hyodyisinteriae; cow footrot related to infection byFusobacterium spp.; cow metritis related to infection by E. coli; cowhairy warts related to Infection by Fusobacterium necrophorum orBacteroides nodosus; cow pink-eye related to infection by Moraxellabovis, cow premature abortion related to infection by protozoa (i.e.neosporium); urinary tract infection in dogs and cats related toinfection by E. coli; skin and soft tissue infections in dogs and catsrelated to infection by S. epidermidis, S. intermedius, coagulase neg.Staphylococcus or P. multocida; and dental or mouth infections in dogsand oats related to infection by Alcaligenes spp., Bacteroides spp.,Clostridium spp., Enterobacter spp., Eubacterium spp.,Peptostreptococcus spp., Porphfyromonas spp., Campylobacter spp.,Actinomyces spp., Erysipelothrix spp., Rhodococcus spp., Trypanosomaspp., Plasmodium spp., Babesia spp., Toxoplasma spp., Pneumocystis spp.,Leishmania spp., and Trichomonas spp. or Prevotella spp. Other bacterialinfections and protozoa infections and disorders related to suchinfections that may be treated or prevented in accord with the method ofthe present invention are referred to in J. P. Sanford at al., “TheSanford Guide To Antimicrobial Therapy,” 26th Edition, (AntimicrobialTherapy, Inc., 1996).

Antibacterial activity studies may be carried out using suitable assaysas are known in the art. Susceptibility tests can be used toquantitatively measure the in vitro activity of an antimicrobial agentagainst a given bacterial isolate. Compounds are tested for in vitroantibacterial activity by a micro-dilution method. Minimal InhibitoryConcentration (MIC) is determined in 96 well microtiter plates utilizingthe appropriate Mueller Hinton Broth medium (CAMHB) for the observedbacterial isolates. Antimicrobial agents are serially diluted (2-fold)in DMSO to produce a concentration range from about 64 μg/ml to about0.03 μg/ml. The diluted compounds (2 μl/well) are then transferred intosterile, uninoculated CAMHB (0.2 mL) by use of a 96 fixed tip-pipettingstation. The inoculum for each bacterial strain is standardized to 5×10⁵CFU/mL by optical comparison to a 0.5 McFarland turbidity standard. Theplates are inoculated with 10 μl/well of adjusted bacterial inoculum.The 96 well plates are covered and incubated at 35+/−2° C. for 24 hoursin ambient air environment. Following incubation, plate wells arevisually examined by Optical Density measurement for the presence ofgrowth (turbidity). The lowest concentration of an antimicrobial agentat which no visible growth occurs is defined as the MIC. The compoundsof the invention generally demonstrated an MIC in the range from about64 μg/ml to about 0.03 μg/ml.

All in vitro testing follows the guidelines described in the ApprovedStandards M7-A4 protocol, published by the National Committee forClinical Laboratory Standards (NCCLS).

The invention further provides compositions and methods of treatingsubjects suffering from an inflammatory condition comprisingadministering to a subject in need thereof, a therapeutically effectiveamount of at least one compound of the invention. Specific examples ofinflammatory conditions treatable according to the invention include,but are not limited to, scleritis; epi-scleritis; allergicconjunctivitis; pulmonary inflammatory diseases, particularly CF,asthma, chronic obstructive pulmonary disease (COPD), allergicbronchopulmonary aspergillosis (ABPA), and sarcoidosis;procto-sigmoiditis; allergic rhinitis; arthritis; tendonitis; apthousstomatitis; and inflammatory bowel disease.

The invention further provides compositions and methods for i)prophylactic treatment of those subjects susceptible to the symptoms CFincluding pulmonary infection and inflammation associated with CF, ii)treatment at the initial onset of symptoms of pulmonary infection andinflammation associated with CF, and iii) treatment of ongoing orrelapsing symptoms of infection and inflammation associated with CF. Inaccordance with the invention a compound of the invention, isadministered to a subject in need of treatment for CF, in amountsufficient to prevent, diminish or eradicate symptoms of CF includingchronic pulmonary inflammation and infection.

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the subject in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43,650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969,incorporated herein by reference.

According to the methods of treatment of the present invention,bacterial infections, cystic fibrosis and inflammatory conditions aretreated or prevented in a subject such as a human or another animal byadministering to the subject a therapeutically effective amount of acompound of the invention, in such amounts and for such time as isnecessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg. Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular subject will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thesubject; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a subject in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the formulae described herein can, for example, beadministered by injection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with pharmaceutically excipients or carriers toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations may contain from about 20% to about 80% activecompound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular subject will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the subject'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Subjects may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

When the compositions of this invention comprise a combination of acompound of the formulae described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

The pharmaceutical compositions of this invention can be administeredorally to fish by blending said pharmaceutical compositions into fishfeed or said pharmaceutical compositions may be dissolved in water inwhich infected fish are placed, a method commonly referred to as amedicated bath. The dosage for the treatment of fish differs dependingupon the purpose of administration (prevention or cure of disease) andtype of administration, size and extent of infection of the fish to betreated. Generally, a dosage of 5-1000 mg, preferably 20-100 mg, per kgof body weight of fish may be administered per day, either at one timeor divided into several times. It will be recognized that theabove-specified dosage is only a general range which may be reduced orincreased depending upon the age, body weight, condition of disease,etc. of the fish.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one of ordinary skill in theart. All publications, patents, published patent applications, and otherreferences mentioned herein are hereby incorporated by reference intheir entirety.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are:

Ac for acetyl;

AIBN for azobisisobutyronitrile;

Bu₃SnH for tributyltin hydride;

CDI for carbonyldiimidazole;

dba for dibenzylidene acetone;

dppb for diphenylphosphino butane;

DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;

DEAD for diethylazodicarboxylate;

DMAP for dimethylaminopyridine;

DMF for dimethyl formamide;

DPPA for diphenylphosphoryl azide;

EtOAc for ethyl acetate;

EtOH for ethanol;

MeOH for methanol;

Ms for mesylate or O—SO₂—CF₃;

NaN(TMS)₂ for sodium bis(trimethylsilyl)amide;

NMMO for N-methylmorpholine N-oxide;

TEA for triethylamine;

THF for tetrahydrofuran;

TPP or PPh₃ for triphenylphosphine;

MOM for methoxymethyl;

Boc for t-butoxycarbonyl;

Bz for benzoyl;

Bn for benzyl;

Ph for phenyl;

POPd for dihydrogendichlorobis(di-tert-butylphosphinito-κP)palladate(II);

TBS for tert-butyl dimethylsilyl; or

TMS for trimethylsilyl.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared.

A preferred intermediate for the preparation of compounds represented byformula I is a compound represented by formula VIII as illustrated below

wherein R_(p), U, V, W, X, Y and Z are as previously defined.

Schemes 1-2 describe processes for the preparation of compoundsaccording to the invention.

Compounds of formula VIII, which are useful as the starting materialsfor the preparation of compounds of the present invention are preparedfrom erythromycin using the procedures described in U.S. Pat. No.6,878,691 and U.S. Patent Application Publication No. 2004/0053861,incorporated herein by reference.

Scheme 1 illustrates a process of preparing compounds of the presentinvention by converting the bridged ketone of VIII into an oxime offormula (1-2) using the appropriate substituted hydroxylamine of theformula:

where A is as previously defined. This oxime formation can beaccomplished, using the appropriate substituted hydroxylamine undereither acidic or basic conditions in a variety of solvents.Representative acids include, but are not limited to, hydrochloric acid,phosphoric acid, sulfuric acid, p-toluenesulfonic acid, and pyridiniump-toluene sulfonate and the likes. Likewise, representative basesinclude, but are not limited to, triethylamine, pyridine,diisopropylethyl amine, 2,6-lutidine, and the likes. Appropriatesolvents include, but are not limited to, methanol, ethanol, water,tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate and the likes.Preferably the reaction is carried out in ethanol using aqueoushydrochloric acid. Reaction temperature is generally, but not limitedto, from −20° C. to 40° C. and the reaction time is from 1 to 8 hours,preferably the reaction is carried out at 0° C.

Scheme 2 illustrates the procedure by which compounds of formula (2-1)may be converted to compounds of formula (2-2) by treatment withisocyanates of formula R1-NCO, acid chlorides of formula R1-C(O)Cl orAlkyl isocyanates in the present of bases such as, but not limited to,sodium hydride, potassium hydride, potassium tert-butoxide, potassiumhydroxide, KHMDS, and the like. The reaction is typically carried out inaprotic solvents such as, but not limited to, THF, DMSO, DMF, or dioxaneand the likes. The temperature of the reaction is from 25° C. to 80° C.The preferred reaction time is from 5 to 20 hours.

Alternatively, some of the ester compounds of formula (2-2) can beprepared by treating compounds of formula (2-1) with acids of formulaR1-C(O)OH in the presence of bases such as but not limited to Et₃N,Pyridine, DMAP and coupling agents such as but not limited to EDC,BOPCl, HATU, and the likes in aprotic solvents such as but not limitedto dichloromethane, ethylene chloride, THF, DMF, acetonitrile and thelike at a temperature from 25° C. to 80° C. and the reaction time isfrom 2 to 24 hours.

Compounds of formula (2-1) also can be treated with substitutedtert-butyl allyl carbonate in the presence of a palladium catalyst and aphosphine additive to give allyl ethers.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1 Step 1a

To a solution of 2-amino-4-methylphenol (157.6 g, 1.28 mol) in 1500 mlof EtOH at room temperature, under stirred condition, was addedbromocyanogen (135.00 g, 1.28 mol) in about 30 minutes. During theaddition, the reaction mixture became warm and water bath was used tocool the reaction to room temperature. After 5-6 hours, the reactionsolvent was evaporated under reduced pressure. The residue was dissolvedin about 1500 ml of EtOAc and washed with the saturated NaHCO₃ (1.5 L).The organic layer was separated and dried over anhydrous MgSO₄. Removalof solvent and dried by high vacuum gave about 150 g of the titlecompound as pale brown color, which can be used in next step. ESI MSm/e: 149 (M+H)⁺.

Step 1b

A solution of succinic anhydride (141.1 g, 1.41 mol) and 70 g (about0.47 mol) of compound of step 1a (70 g, 0.47 mol) in 2500 ml ofanhydrous toluene was refluxed for overnight. After that, HATU (100 g,0.26 mol) and 4-methylmorpholine (41.36 ml, 0.376 mol) were added andthe resulting mixture was refluxed for 2-3 hours. TLC showed that themajor spot was product (Rf=0.35, acetone:hexane=1:2). After reaction wascompleted, the solvent was evaporated and the residue was dissolved inabout 2000 ml of CH₂Cl₂. The solution was washed with aqueous NaHCO₃.After pH was adjusted to 7-8 and washed with brine, organic phase wasseparated and dried over MgSO₄. Filtration and removal of solvent gavethe title compound (98 g) as fine white needle crystalline ESI MS m/e:231 (M+H)⁺.

Step 1c

To a solution of the compound of step 1b (44.37 g, 0.193 mol) in CCl₄(1.5 L) was added NBS (41.16 g, 0.23 mol) and then the mixture wereheated to reflux. Benzoyl peroxide (0.75 g) was added by three times.After refluxing for 24 hours, the reaction was cooled to roomtemperature and the mixture was diluted with 1.5 L of CH₂Cl₂. Theorganic phase was separated and washed with 4 L of saturated NaHCO₃ twotimes to adjust pH to 7-8. Dried over MgSO₄ and removal of the solventunder reduced pressure gave the title compound (57.3 g) as slight yellowsolid which was used for next step without further purification. ESI MSm/e: 309/311 (M+H)⁺.

Step 1d

To a solution of the compound of step 1c (57.3 g, 0.185 mol) in 450 mlof MeCN were added N-hydroxyphanthalimide (60.51 g, 0.371 mol) and 80 mlof triethylamine. The reaction mixture was stirred at 50° C. for 5 hoursand cooled to room temperature. The reaction was added water (200 ml)and filtered. The pale yellow solid was collected, washed with 100 ml ofMeOH and ether in the 1:1 ratio. Dried on vacuum to give the titlecompound (48 g) as pale solid. ESI MS m/e: 392 (M+H)⁺.

Step 1e

A mixture of the compound of step 1d (39.1 g, 0.1 mol) in 500 ml of 2Mammonia in methanol was stirred at room temperature for 16 hours andfiltered. The filtrate was concentrated and purified on silica gel (2MNH₃ in MeOH:CH₂Cl₂=5:95) to give the title compound (17 g, 95%). ESI MSm/e: 180 (M+H)⁺.

Step 1f

To a solution of compound of step 1d (215 mg, 1.2 mmol) in 15 ml ofethanol was added 1N HCl (2 ml). The mixture was cooled to 0° C. andadded compound of formula VIII where X and Y taken together with theatom that they are attached is C═N—Ac and U and V taken together withthe atom that they are attached is C═O, Z=H, R_(p)═Ac and W═NMe₂ (711mg, 1 mmol). The mixture was stirred at 0° C. for 1 hour and quenchedwith saturated NaHCO₃ (50 ml). Extracted with ethyl acetate (100 ml) andwashed with brine (100 ml×2). Dried over anhydrous Na₂SO₄ andconcentrated to give crude title compound (828 mg, 95%, as a mixture ofoximes, oximeE/Z=4/1), which was used for next step reaction withoutfurther purification. ESI MS m/e: 872 (M+H)⁺.

Step 1g

A solution of compound of step 1f (828 mg, 0.95 mmol) in 15 ml ofmethanol was stirred at 60° C. for 5 hours. The solvent was removed andthe residue was purified on silica gel (2M NH₃ in MeOH/CH₂Cl₂=5/95) togive the title compound (765 mg, 97%, as a mixture of E/Z oximesE/Z˜4/1). The compound was further separated on HPLC to give E-oximeisomer (430 mg) and Z-oxime isomer (110 mg).

E-oxime isomer: ESI MS m/e: 830 (M+H)⁺.

E-oxime isomer: ¹³C NMR (125 MHz, CDCl₃): δ 205.9, 191.4, 186.8, 184.7,178.1, 167.8, 162.1, 153.3, 148.5, 143.0, 134.1, 125.6, 121.9, 116.8,108.7, 103.0, 79.4, 76.4, 74.6, 70.5, 69.8, 66.1, 63.2, 62.9, 50.8,40.5, 38.8, 31.2, 28.5, 25.3, 23.8, 21.5, 19.5, 17.8, 15.1, 14.1, 12.8.

Z-oxime isomer: ESI MS m/e: 830 (M+H)⁺.

Z-oxime isomer: ¹³C NMR (125 MHz, CDCl₃): δ 206.2, 184.7, 176.9, 169.3,163.0, 155.9, 148.5, 143.2, 133.6, 121.6, 116.7, 108.5, 103.0, 79.5,79.0, 76.7, 76.2, 75.8, 70.5, 70.2, 69.7, 66.1, 58.2, 53.7, 51.0, 45.3,40.5, 39.7, 39.0, 36.9, 28.5, 25.5, 23.4, 21.5, 20.3, 19.6, 17.3, 15.7,14.5, 12.9, 12.0.

Example 2 Step 2a

The title compound of step 2a was prepared according to experimentalprocedure from U.S. Pat. No. 6,878,691 incorporated herein by reference.

Step 2b

To a solution of compound of step 2a (711 mg, 1 mmol) in 8 ml ofacetonitrile was added 1 N HCl (10 ml) at room temperature. The mixturewas stirred at room temperature for 4 hours and was quenched withsaturated NaHCO₃ (30 ml). Extracted with ethyl acetate (40 ml) and theorganic phase was washed with brine (40 mlX2). After dried overanhydrous Na₂SO₄, the solvent was removed and the residue was purifiedon silica gel column (hexane:acetone=1:1) to give the title compound(330 mg, 49%).

Step 2c

To a solution of compound from step 2b (215 mg, 1.2 mmol) in 15 ml ofethanol was added 1N HCl (2 ml). The mixture was cooled to 0° C. andadded bridged ketone ketolide, compound of step 2a (670 mg, 1 mmol). Themixture was stirred at 0° C. for 1 hour and quenched with saturatedNaHCO₃ (50 ml). Extracted with ethyl acetate (100 ml) and washed withbrine (100 ml×2). Dried over anhydrous Na₂SO₄ and concentrated to givecrude title compound (764 mg, 92%, E/Z˜1/1). ESI MS m/e: 831 (M+H)⁺.

Step 2d

A solution of compound of step 2c (764 mg, 0.92 mmol) in 15 ml ofmethanol was stirred at 60° C. for 6 hours. The solvent was removed andthe residue was purified on silica gel (2M NH₃ in MeOH/CH₂Cl₂=5/95) togive the title compound as a mixture of E/Z oxime isomers (690 mg, 95%,E/Z˜1/1). The compound was further separated on HPLC to give E-oximeisomer (280 mg) and Z-oxime isomer (230 mg).

E-oxime isomer: ESI MS m/e: 789 (M+H)⁺.

E-oxime isomer: ¹³C NMR (125 MHz, CDCl₃): δ 218.5, 205.6, 191.7, 168.0,162.0, 152.8, 148.6, 143.0, 134.0, 122.1, 117.0, 108.7, 103.3, 79.3,79.0, 76.5, 75.8, 74.5, 70.5, 69.8, 66.1, 63.0, 61.5, 51.0, 47.0, 46.2,40.5, 39.5, 39.3, 28.5, 23.5, 21.4, 20.0, 18.6, 18.0, 14.6, 14.2, 12.6,12.2.

Z-oxime isomer: ESI MS m/e: 789 (M+H)⁺.

Z-oxime isomer: ¹³C NMR (125 MHz, CDCl₃): δ 215.0, 205.7, 169.6, 162.2,156.2, 149.0, 142.8, 131.4, 124.8, 116.3, 109.7, 102.5, 79.9, 78.7,76.3, 76.2, 70.5, 69.7, 66.1, 59.2, 50.8, 46.3, 45.7, 40.5, 40.0, 39.1,28.5, 23.1, 21.6, 19.7, 18.5, 17.2, 14.5, 13.1, 12.9, 11.8.

Example 3

In accordance with Schemes 1 and 2, the following compounds of theinvention having the Formula II were prepared:

wherein A, Q and Z are defined as in Table I.

TABLE I MS (ESI): Example A- Q Z m/z (M + H)⁺ ¹³C NMR (125 MHz, CDCl₃):δ Example 01

NAc H 831 205.8, 184.7, 178.0, 167.8, 154.3, 153.8,153.0, 136.0, 134.0,126.7, 123.5, 121.5,103.1, 79.3, 79.2, 76.8, 75.8, 75.5, 74.7,70.5,69.7, 66.1, 63.1, 62.9, 50.7, 46.2, 40.5,38.8, 37.2, 31.2, 28.5, 25.3,23.8, 21.5, 20.3,19.5, 17.8, 15.1, 14.1 Example 02

NAc F 864 Example 03

NAc H 832 Example 04

NAc H 846 Example 05

NAc H 815 205.8, 184.7, 178.0, 167.8, 153.6, 153.0,149.8, 140.3, 135.0,126.3, 120.5, 110.8,103.0, 79.4, 76.8, 76.0, 74.6, 70.5, 69.7,66.1,63.1, 62.8, 53.7, 50.7, 46.2, 40.5, 38.9,28.5, 25.3, 23.8, 21.5, 20.3,19.5, 17.8, 15.1,14.1, 13.6, 12.9 Example 06

NAc H 830 Example 07

NAc H 830 Example 08

NAc F 848 (selected) 205.5, 205.3, 184.2, 165.1, 164.9,162.4, 153.7,148.8, 142.7, 131.2, 124.5,116.2, 109.3, 104.1, 99.7, 98.1, 79.7,76.5,73.7, 70.6, 69.8, 66.0, 63.1, 62.6, 41.2, 40.5,39.0, 28.4, 25.3,24.7, 24.5, 23.2, 21.4, 21.0,17.5, 15.0, 14.3, 12.6 Example 09

O H 805 218.4, 205.6, 168.0, 166.3, 152.0, 132.1,131.9, 126.9, 121.5,119.1, 103.3, 79.3, 78.9,76.4, 75.9, 74.6, 70.5, 69.8, 66.1, 13.0,61.5,50.9, 47.1, 46.2, 40.5, 39.5, 39.3, 28.5, 23.5,21.5, 20.1, 18.6,18.0, 14.6, 14.2, 12.6, 12.2. Example 10

NAc H 830 205.9, 184.7, 178.0, 167.9, 162.2, 153.4,148.9, 142.6, 131.5,124.6, 116.2, 109.4,103.1, 79.3, 76.8, 74.8, 70.5, 66.1, 63.2,62.9,50.8, 40.5, 38.8, 28.5, 25.4, 23.8, 21.5,20.3, 19.6, 17.8, 15.1, 14.1,12.8. Example 11

O H 789 216.3, 203.6, 165.9, 160.1, 150.8, 146.8,140.6, 129.1, 122.7,114.1, 107.5, 101.2,77.2, 76.8, 74.7, 74.4, 73.8, 72.6, 68.4, 67.7,63.9,60.8, 59.4, 51.5, 48.9, 45.0, 44.0, 38.3,37.4, 29.0, 26.3, 21.3, 19.3,18.0, 16.4, 15.9,12.6, 12.1 Example 12

NAc H 889 (selected): 205.8, 185.0, 178.3, 168.2, 161.6,155.9, 153.4,148.9, 133.0, 131.6, 126.6,121.2, 120.0, 103.0, 79.4, 76.7, 76.2,70.5,69.7, 66.0, 63.2, 50.8, 46.2, 40.5, 38.8, 28.5,25.5, 23.7, 21.5,20.2, 19.7, 18.0, 15.4, 14.1,13.7, 12.7. Example 13

NAc H 864 (selected): 205.9, 184.7, 178.0, 167.9, 167.4,153.9, 153.7,152.0, 140.1, 140.0, 133.7,132.9, 132.8, 116.4, 112.4, 112.3,103.0,79.3, 76.7, 75.6, 74.8, 70.5, 59.7, 66.0, 63.1,62.9, 50.8, 46.3,40.4, 38.8, 28.5, 25.3, 23.7,21.5, 20.3, 19.6, 17.8, 15.1, 14.1, 13.7,12.8 Example 14

O H 848 (selected); 217.9, 205.6, 168.9, 162.0, 155.5,152.9, 131.8,126.8, 122.1, 119.7, 102.8, 9.4,79.3, 76.5, 75.1, 70.5, 69.8, 66.1,63.2, 50.9,46.6, 46.3, 40.5, 39.4, 28.5, 23.2, 21.5, 18.2,17.9, 14.2,14.0, 13.2, 12.2. Example 15

O H 823 (selected): 218.4, 205.7, 168.1, 167.4, 154.0,153.1, 152.0,140.2, 140.0, 133.8, 133.7,132.8, 132.7, 116.7, 112.7, 112.5,103.3,79.3, 78.9, 76.8, 75.9, 75.8, 74.7, 70.5, 69.8,66.0, 62.9, 61.5,51.0, 47.2, 46.2, 40.4, 39.4,39.3, 28.5, 23.5, 21.5, 20.1, 18.5, 18.0,14.7,14.2, 12.5, 12.2 Example 16

NAc H 829 Example 17

NAc H 830 205.9, 191.4, 186.8, 184.7, 178.1, 167.8,162.1, 153.3, 148.5,143.0, 134.1, 125.6,121.9, 116.8, 108.7, 103.0, 79.4, 76.4, 74.6,70.5,69.8, 66.1, 63.2, 62.9, 50.8, 40.5, 38.8,31.2, 28.5, 25.3, 23.8, 21.5,19.5, 17.8, 15.1,14.1, 12.8. Example 18

O H 789 218.5, 205.6, 191.7, 168.0, 162.0, 152.8,148.6, 143.0, 134.0,122.1, 117.0, 108.7,103.3, 79.3, 79.0, 76.5, 75.8, 74.5, 70.5,69.8,66.1, 63.0, 61.5, 51.0, 47.0, 46.2, 40.5,39.5, 39.3, 28.5, 23.5, 21.4,20.0, 18.6, 18.0,14.6, 14.2, 12.6, 12.2. Example 19

NAc H 888 Example 20

NAc H 830 Example 21

NAc F 848 Example 22

NAc F 847 Example 23

NAc H 829 (selected); 206.2, 184.8, 168.6, 155.0, 153.8,110.0, 103.4,79.5, 76.7, 75.1, 70.5, 69.8,66.0, 63.2, 63.0, 51.3, 40.5, 38.8, 31.2,30.0,28.4, 25.4, 23.7, 21.8, 20.6, 20.0, 17.9, 15.1,14.1, 12.8. Example24

O H 788 (selected): 218.5, 206.0, 168.8, 155.1, 153.3,129.8, 121.1,103.4, 79.6, 79.1, 76.6, 75.4,70.6, 69.8, 66.0, 62.9, 62.1, 53.7, 51.4,47.6,46.0, 40.5, 39.7, 39.4, 28.4, 23.4, 21.5, 20.4,18.6, 18.2, 15.3,14.4, 12.5, 12.2. Example 25

NAc H 897 205.8, 184.8, 178.0, 167.9,167.8, 159.3, 153.5,153.3, 146.3,143.8, 143.7,135.0, 133.9, 1333.3,125.4, 123.7, 121.9, 120.2,111.1,103.0, 79.4,79.2, 76.5, 76.4, 74.8, 70.5, 69.8,66.1, 63.2, 62.9,50.8,46.2, 40.5, 38.8, 28.5,25.4, 23.8, 21.5, 20.3,19.6, 17.8, 15.1, 14.1,13.7, 12.9. Example 26

NAc H 815 205.8, 184.7, 178.0, 167.8, 153.6, 153.0,149.8, 140.3, 135.0,126.3, 120.5, 110.8,103.0, 78.4, 76.0, 74.6, 70.5, 69.7, 66.2,63.1,62.9, 50.7, 46.2, 40.5, 38.8, 28.6, 25.4,23.8, 21.5, 20.3, 19.5, 17.8,15.1, 14.1, 13.6,12.9 Example 27

O H 775 218.4, 205.6, 168.0, 153.0, 149.8, 140.3,134.9, 126.5, 120.7,110.8, 103.1, 79.3, 79.0,76.1, 75.8, 74.6, 70.5, 69.6, 66.2, 63.0,61.5,50.9, 47.0, 46.2, 40.5, 39.5, 39.3, 28.9, 23.5,21.4, 20.0, 18.6,18.0, 14.6, 14.3, 12.6, 12.2 Example 28

NAc H 898 205.8, 184.7, 178.0, 167.8,157.5, 155.1, 153.7,150.5, 145.3,141.6, 135.9,127.1, 123.3, 120.4,111.1, 103.0, 79.4, 76.8, 75.8,74.6,70.5, 69.7,66.1, 63.1, 62.9, 50.7, 40.5, 38.8,29.9, 29.5, 28.5,25.4,23.8, 21.5, 20.3, 19.5,17.8, 15.1, 14.1, 13.6,12.9. Example 29

NAc H 881 Example 30

NAc H 845 Example 31

NAc H 870 (selected): 210.1, 184.7, 177.9, 170.0, 162.4,153.7, 148.5,143.1, 133.9, 132.9, 121.5,119.6, 116.4, 108.7, 102.4, 81.2, 79.7,76.6,76.3, 74.5, 70.6, 69.5, 66.2, 62.7, 60.8, 43.7,40.7, 40.5, 40.1,39.3, 37.4, 29.0, 25.3,22.7, 21.6, 21.4, 20.6, 19.8, 18.3, 16.2,14.8,12.5. Example 32

NAc H 806 (selected): 206.1, 184.9,178.0, 168.1, 153.8,150.1, 120.4,113.7,103.0, 79.4, 76.7, 70.5,69.7, 66.0, 50.9, 40.5,28.7, 25.4, 23.7,21.5, 17.8,17.2, 15.7, 15.1, 14.1, 12.8, 12.0. Example 33

NAc H 816 Example 34

NAc H 831 (selected): 205.9, 184.8, 177.9, 167.9, 165.1,157.6, 153.8,152.9, 140.5, 115.5, 114.9,102.9, 79.3, 76.8, 76.7, 75.1, 70.5,69.6,66.1, 63.1, 50.9, 40.5, 38.8, 28.7, 25.6, 25.4,23.8, 21.6, 21.5,20.4, 19.6, 17.8, 17.2, 15.2,14.1, 12.8, 12.0. Example 35

NAc H 910 (selected): 209.9, 184.7, 177.8, 169.9, 157.6,153.9, 144.3,133.6, 133.3, 132.8, 131.0,121.1, 119.7, 118.1, 108.5, 107.6,102.4,81.0, 79.7, 76.5, 76.0, 74.4, 70.5, 69.5, 66.3,62.7, 62.6, 60.7,45.1, 43.7, 40.6, 39.3, 29.2,25.3, 22.9, 21.5, 20.6, 19.8, 18.2, 16.3,14.7,12.7. Example 36

NAc H 815 Example 37

NAc H 829 Example 38

NC(O)OCH₃ H 846 205.9, 186.4, 167.7, 163.7,162.4, 153.2, 148.4,143.0,134.1, 121.8, 116.6,108.7, 102.9, 79.5, 78.977.5, 76.8, 76.4, 75.1,74.7,70.5, 69.7, 66.1, 63.262.7, 54.1, 53.1, 50.7, 40.5,38.7, 32.0,29.5, 28.623.8, 21.5, 20.2, 19.3,17.8, 14.9, 14.1, 12.9, Example 39

NH H 788 205.2, 169.3, 162.8, 153.7, 148.5, 143.1,133.7, 121.6, 116.5,108.8,103.5, 80.4, 78.8,78.6, 76.6, 75.9, 70.6, 69.8,66.1, 64.7,63.1,51.6, 47.9, 41.4, 40.5, 38.3, 28.5, 23.0, 21.4,21.1, 20.1, 17.4,15.8,14.4, 14.0, 11.8In accordance with Scheme 1, compounds of the invention having theFormula IX were prepared:

wherein A, Q, and Z are defined as in Table II.

TABLE II MS (ESI): Example A- Q Z m/z (M + H)⁺ ¹³C NMR (125 MHz, CDCl₃):δ Example 01

NAc H 815 205.8, 184.6, 176.5, 169.3, 156.2, 153.0, 149.9,140.3, 134.8,126.6, 120.8, 110.9, 102.6, 79.6,79.0, 76.3, 76.2, 70.5, 69.7,66.1,58.4, 50.9, 45.4,40.5, 29.9, 28.6, 25.5, 23.4, 21.6,20.2, 19.7,17.2,15.6, 14.4, 12.9, 12.0 Example 02

O H 805 215.1, 205.7, 169.6, 166.8,156.2, 152.1, 132.0,126.6, 121.3,118.9, 102.5, 80.0, 78.7, 76.3, 76.1,70.5, 69.7, 66.0, 50.8, 46.3, 45.7,40.4, 40.0, 39.1,28.5, 23.1, 21.6, 19.7, 18.5, 17.3, 14.5, 13.1, 11.8Example 03

O H 789 215.0, 205.7, 169.6, 162.2, 156.2, 149.0, 142.8,131.4, 124.8,116.3, 109.7, 102.5, 79.9, 78.7,76.3, 76.2, 70.5, 69.7, 66.1, 59.2,50.8, 46.3, 45.7,40.5, 40.0, 39.1, 28.5, 23.1, 21.6, 19.7, 18.5,17.2,14.5, 13.1, 12.9, 11.8. Example 04

NAc H 864 (selected): 205.9, 184.6, 176.4, 169.4, 166.7,156.4, 154.2,152.2, 140.1, 140.0, 134.0, 133.9,133.3, 133.2, 116.6, 116.5, 112.6,112.4, 102.6,79.6, 79.0, 76.2, 75.8, 75.4, 70.5, 69.7, 66.1, 58.5,50.9,45.4, 40.5, 39.0, 28.5, 25.5, 23.3, 21.6, 20.2,19.7, 17.2, 15.7, 14.4,13.0, 12.0. Example 05

O H 848 (selected): 216.3, 205.4, 169.6, 162.0, 155.8,149.0, 131.9,127.1, 119.6, 102.3, 80.0, 79.0,76.7, 76.3, 76.0, 70.5, 69.7, 66.0,59.4, 50.7, 46.3,45.7, 40.5, 40.1, 39.3, 29.9, 28.6, 23.1, 21.6,19.8,18.2, 17.4, 14.5, 13.7, 13.0, 11.7. Example 06

O H 823 (selected): 215.2, 205.7, 169.6, 167.2, 156.5,154.1, 152.1,140.2, 140.1, 134.0, 133.9, 133.0,132.9, 116.6, 112.5, 112.3, 102.5,76.3, 70.5,69.7, 66.1, 59.1, 50.9, 46.3, 45.7, 40.5, 39.2, 28.5,23.1,21.6, 19.7, 18.5, 17.2, 14.5, 13.2, 12.8, 11.8 Example 07

NAc H 830

In accordance with Scheme I, compounds of the invention having theFormula X were prepared:

wherein A, X and Z are defined as in Table III.

TABLE III MS (ESI): m/z (M + Example A- X Z H)⁺ Example 01

NH₂ H 790

Example 4

Step 4a

A solution of 5-bromo-2-thiophenecarboxaldehyde (13.08 g, 68.46 mmol) inisopropanol (100 mL) was treated with NaBH₄ (1.30 g, 34.23 mmol) at 0°C. for 1.5 hours with stirring before HCl (1 M, 60 mL, 60 mmol) wascharged. The mixture was stirred for 0.5 hour before being partitioned(ethyl acetate and saturated NaHCO₃). The organics were washed withwater, brine, and then dried (Na₂SO₄). The volatile was removed byevaporation and dried in a vacuum to give the title compound (12.55 g,95%).

Step 4b

Into a solution of the compound of Step 4a (5.02 g, 26.00 mmol) in THF(80 mL) was treated with NaH (95%, 730 mg, 28.9 mmol) at roomtemperature for 50 minutes with stirring. It was chilled to −78° C.before n-BuLi (1.6 M in hexanes, 20 mL, 32 mmol) was charged. Themixture was kept at −78° C. for 1 hour before n-Bu₃SnCl (17.6 mL, 65mmol) was introduced. The mixture was warmed up naturally to roomtemperature and stirred over night. The volatile was evaporated off andthe residue was partitioned (ethyl acetate and saturated NaHCO₃). Theorganics were washed with water, brine, and then dried (Na₂SO₄).Evaporation followed by chromatography (silica, hexanes/ethyl acetate)gave the title compound (4.51 g, 43%).

Step 4c

Into a 250 mL round bottom flask was charged 2-amino-6-bromopyridine(25.0 g, 0.144 mol) and phthalic anhydride (21.4 g, 0.144 mol). Thesolid mixture in the open flask (with a slow flow of N₂) was heated to175° C. and the temperature was kept there for 1 hour or until no vaporcomes out. It was cooled down to room temperature and vacuumed for 10hours to give the title compound as a tan solid (100% yield).

Step 4d

A mixture of the compound from Step 4b (4.50 g, 11.16 mmol), thecompound from Step 4c (3.72 g, 12.28 mmol), and Pd(PPh₃)₄ (645 mg, 0.56mmol) in PhMe (50 mL) was degassed and heated at 100° C. under N₂ for 17hours before being cooled to 0° C. The insoluble was collected byfiltration and washed with PhMe to give the title compound (2.90 g). Thefiltrate and washings were evaporated and the residue waschromatographed (silica, hexanes/ethyl acetate) to give another crop ofthe title compound (0.20 g).

ESIMS m/e: 337 (M+H)⁺.

Step 4e

A suspension of the compound from Step 4d (3.10 g, 9.22 mmol) inmethylene chloride (50 mL) was treated with thionyl chloride (3.35 mL,46.08 mmol) at 0° C. The mixture was warmed up naturally to roomtemperature and stirred for 16 hours. The volatile was evaporated off.The residue was partitioned (CH₂Cl₂/saturated NaHCO₃). The organics werewashed with water, brine, and then dried (Na₂SO₄). The volatile wasremoved by evaporation and dried in vacuo to give the title compound(3.253 g, 100%).

ESIMS m/e: 355/357 (M+H)⁺.

Step 4f

Into a solution of N-hydroxylphthalimide (2.40 g, 14.7 mmol) in DMF (20mL) was added NaH (95%, 332 mg, 13.8 mmol) at 0° C. It was warmed up toroom temperature and stirred for 1 hour. It was added into a solution ofthe compound from Step 4e (3.25 g, 9.2 mmol) in DMF (25 mL). The mixturewas stirred at 40° C. for 16 hours before being cooled to roomtemperature. It was diluted with saturated NaHCO₃ and water. Theinsoluble was collected by filtration, washed with saturated NaHCO₃ andwater, and dried to give the title compound (3.930 g, 89%).

ESIMS m/e: 482 (M+H)⁺.

Step 4g

A suspension of the compound from Step 4f (1.00 g, 2.08 mmol) inmethanolic ammonia (2M, 20 mL, 40 mmol) was heated at 55° C. for 2 hoursbefore being cooled to room temperature. The insoluble was filtered offand washed with MeOH. The combined filtrate and washings wereevaporated. The residue was added CH₂Cl₂ to dissolve the crude titlecompound (548 mg) after evaporation.

ESIMS m/e: 222 (M+H)⁺.

Step 4h

A mixture of compound of formula VIII where X and Y taken together withthe atom that they are attached is C═N—Ac, U═H, V═OH, Z=H, Rp=Ac andW═NMe₂ (356 mg, 0.50 mmol), 2-pyridylacetic acid hydrochloride (174 mg,1.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcabodiimide hydrochloride(EDC.HCl, 192 mg, 1.0 mmol), triethylamine (0.28 mL, 2.0 mmol) and DMAP(10.0 mg) in methylene chloride (5.0 mL) was stirred at room temperaturefor 22 hours before more 2-pyridylacetic acid hydrochloride (87 mg, 0.5mmol) and EDC.HCl (192 mg, 1.0 mmol). It was stirred for another 3 hoursbefore being partitioned (ethyl acetate and 10% K₂CO₃). The organicswere washed with water, brine, and then dried (Na₂SO₄). The volatile wasremoved by evaporation and dried in a vacuum to give a yellow foam (450mg) as the crude title compound.

ESIMS m/e: 832 (M+H)⁺.

Step 4i

Into a solution of the crude compound from Step 4 g (166 mg, ˜0.62 mmol)in ethanol (5.0 mL) and HCl (1 M, 2.5 mL) at −5° C. was added the crudecompound from Step 4h (450 mg, 0.5 mmol at most). After being stirredfor one hour, more crude compound from Step 4g (50 mg, ˜0.18 mmol) wasadded. The mixture was stirred for another 1 hour before partition(ethyl acetate and saturated NaHCO₃). The organics were washed withwater, brine, and then dried (Na₂SO₄). It was evaporated and the residuewas chromatographed (silica, hexanes/acetone) to give the title compound(332 mg, 64%) as a 2:1 mixture.

ESIMS m/e: 1035 (M+H)⁺.

Step 4j

A solution of the compound from Step 4i (100 mg) in MeOH (3 mL) wasstirred at room temperature for 70 hours before evaporation to give thetitle compound. The two bridged oxime isomers were separated by HPLC.

E-oxime isomer: ESIMS m/e: 993 (M+H)⁺. ¹³C NMR (CDCl₃, 125 MHz): 184.6,178.0, 172.5, 170.4, 158.0, 153.9, 153.2, 151.0, 149.1, 145.4, 141.8,138.1, 136.6, 127.5, 124.4, 123.7, 122.3, 109.1, 106.7, 103.0, 82.3,79.4, 78.5, 78.3, 76.4, 75.0, 70.8, 70.5, 69.1, 65.4, 63.1, 62.4, 43.8,42.7, 40.4, 39.9, 38.3, 36.8, 35.8, 29.7, 29.2, 25.1, 23.2, 21.0, 19.9,19.1, 17.5, 15.0, 14.3, 12.1, 9.0.

Z-oxime isomer: ESIMS m/e: 993 (M+H)⁺. ¹³C NMR (CDCl₃, 125 MHz): 184.4,176.6, 173.7, 170.2, 158.0, 156.1, 153.9, 151.1, 149.1, 145.5, 141.2,138.1, 136.6, 128.0, 124.4, 123.8, 122.3, 109.1, 106.7, 103.0, 83.3,80.2, 79.0, 77.7, 77.5, 75.8, 70.8, 70.6, 70.5, 69.1, 65.4, 58.7, 43.2,40.3, 39.1, 38.5, 36.5, 36.0, 29.7, 29.2, 25.2, 22.7, 21.1, 20.1, 19.6,16.8, 15.4, 14.6, 11.3, 9.1.

Example 5 Compounds with Improved Antibacterial Activities

Table IV below provides MIC data of species from U.S. Pat. No. 6,878,691and U.S. Patent Application Publication No. 2004/0053861.

The values in the table are minimum inhibition concentration (MIC) andare expressed as ug/mL.

Assays for MIC are described above.

TABLE IV S. S. S. S. S. S. S. aure- aure- aure- pneumo- pneumo- pyo-pyo- H. Com- us us us niae niae genes genes influenzae pound Structure29213 27660 33591 7701 700906 1323 2912 33929 A1

0.25 0.13 >64 0.5 0.25 0.5 8 8 A2

0.5 0.25 >64 0.5 0.25 1 16 16 A3

0.25 0.25 >64 2 0.13 16 32 8 A4

8 64 64 >64 A5

>64 2 64 >64 >64 A6

1 1 16 1 8 2 8 >64

Table V provides data for compounds of this invention demonstratingimproved microbiological activities against gram negative bacteria andresistant organism. The values in Table V are minimum inhibitionconcentration and are expressed as ug/mL.

TABLE V S. S. S. S. pneu- S. pneu- S. S. H. aure- aure- aure- mo- mo-pyo- pyo- influ- Com- us us us niae niae genes genes enzae poundStructure 29213 27660 33591 7701 700906 1323 2912 33929 B1

<=0.06 <=0.06 >64 <=0.06 1 0.25 4 2 B2

0.125 <=0.06 >64 0.125 0.5 0.5 2 2 B3

<=0.06 <=0.06 32 0.125 0.25 0.5 4 2 B4

0.125 0.125 32 0.125 0.125 0.5 1 4

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. All UnitedStates patents and published or unpublished United States patentapplications cited herein are incorporated by reference. All publishedforeign patents and patent applications cited herein are herebyincorporated by reference. All other published references, documents,manuscripts and scientific literature cited herein are herebyincorporated by reference.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound represented by formula:

or their racemates, enantiomers, regioisomers, salts, esters or prodrugsthereof, wherein X and Y are independently selected from the groupconsisting of: hydrogen, deuterium, halogen, R₁, OR₁, S(O)_(n)R₁,—NR₁C(O)R₂, —NR₁C(O)NR₃R₄, —NR₁S(O)_(n)R₂, —C(O)NR₃R₄, and —NR₃R₄; Eachof R₁ and R₂ is independently selected from the group consisting of:hydrogen, acyl, silane, a substituted or unsubstituted, saturated orunsaturated aliphatic group, a substituted or unsubstituted, saturatedor unsaturated alicyclic group, a substituted or unsubstituted aromaticgroup, a substituted or unsubstituted heteroaromatic group, or asubstituted or unsubstituted heterocyclic group; Each of R₃ and R₄ isindependently selected from the group consisting of: hydrogen, acyl, asubstituted or unsubstituted, saturated or unsaturated aliphatic group,a substituted or unsubstituted, saturated or unsaturated alicyclicgroup, a substituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group, a substituted, or unsubstitutedheterocyclic group; or can be taken together with the nitrogen atom towhich they are attached to form a substituted or unsubstitutedheterocyclic or heteroaromatic ring; or X and Y, taken together with thecarbon atom to which they are attached, are selected from the groupconsisting of: CO, C═CHR₁, C═NR₁, C═NC(O)R₁, C═NOR₁, C═NO(CH₂)_(m)R₁,C═NNHR₁, C═NNHCOR₁, C═NNHCONR₁R₂, C═NNHS(O)_(n)R₁, C═N—N═CHR₁, C═N—NO₂,or C═N—ONO; one of U or V is hydrogen and the other is independentlyselected from the group consisting of: R₁, OR₁, OC(O)R₁, OC(O)NR₃R₄,S(O)_(n)R₁,

or U and V, taken together with the carbon atom to which they areattached, are C═O; one of J or G is hydrogen and the other is selectedfrom: R₁, OR₁, or NR₃R₄; or, J and G, taken together with the carbonatom to which they are attached, are selected from: C═O, C═NR₁, C═NOR₁,C═NO(CH₂)_(m)R₁, C═NNHR₁, C═NNHCOR₁, C═NNHCONR₁R₂, C═NNHS(O)_(n)R₁, orC═N—N═CHR₁; L is selected from the group consisting of: hydrogen, asubstituted or unsubstituted, saturated or unsaturated aliphatic group,a substituted or unsubstituted, saturated or unsaturated alicyclicgroup, a substituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group, or a substituted or unsubstitutedheterocyclic group; M is R₁; W is NR₃R₄; Z is hydrogen, alkyl orhalogen; R_(p) is hydrogen, hydroxy protecting group or hydroxy prodruggroup; m is an integer; and n is 0, 1, or
 2. A is

wherein: Q′ is N, CH or CF; X₁ is O, N, NR₁, S, or CR₅; Y₁ is O, N, NR₁,S, CR₅, or Se; Z₁ is O, N, NR₁, S, or CR₅; R₅ is independently selectedfrom hydrogen, acyl, silane, a substituted or unsubstituted, saturatedor unsaturated aliphatic group, a substituted or unsubstituted,saturated or unsaturated alicyclic group, a substituted or unsubstitutedaromatic group, a substituted or unsubstituted heteroaromatic group, asubstituted or unsubstituted heterocyclic group, NR₃R₄, OH, NHCOR₁ orNHCONH₂, and is preferably, NH₂ or NHR₁. With the proviso that acompound of Formula I is not selected from the following compound whereA, Q, and Z as defined below in the Table A. TABLE A

Compound A Q Z 01

NAc H 02

NAc H 03

NH H 04

NAc H


2. A compound of claim 1 wherein A is:

wherein X₁ and R₅ are as previously defined in claim
 1. 3. A compound ofclaim 1 wherein A is:

wherein X₁ is O or S, and R₅ is as previously defined in claim
 1. 4. Acompound of claim 1 wherein A is:

wherein X₁ is O or S, and R₅ is as previously defined in claim
 1. 5. Acompound of claim 1 wherein A is:

wherein R₅ is as previously defined in claim
 1. 6. A compound of claim 1wherein A is:


7. A compound of claim 1 wherein A is selected from the compounds shownin Table B. TABLE B Number A- 01

02

03

04

05

06

07

08

09

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33


8. A compound of claim 1 having the Formula II:

wherein A, Q, and Z are as defined in Table C: TABLE C Num- ber A Q Z 01

NAc H 02

NAc F 03

NAc H 04

NAc H 05

NAc H 06

NAc H 07

NAc H 08

NAc F 09

O H 10

NAc H 11

O H 12

NAc H 13

NAc H 14

O H 15

O H 16

NAc H 17

NAc H 18

O H 19

NAc H 20

NAc H 21

NAc F 22

NAc F 23

NAc H 24

O H 25

NAc H 26

NAc H 27

NAc H 28

O H 29

NAc H 30

NAc H 31

NAc H 32

NAc H 33

NAc H 34

NAc H 35

NAc H 36

NAc H 37

NAc H 38

NC(O)OCH₃ H 39

NH H


9. A compound of claim 1 having the Formula III:

wherein R_(p), U, V, X, Y, L, W and Z are as previously defined inclaim
 1. 10. A pharmaceutical composition comprising a compound of claim1 or a pharmaceutically acceptable salt, ester or prodrug thereof, incombination with a pharmaceutically acceptable carrier.
 11. A method oftreating a bacterial infection in a subject in need of such treatmentcomprising, administering to said subject a pharmaceutical compositionof claim
 10. 12. A method of treating inflammation in a subject in needof such treatment comprising, administering to said subject apharmaceutical composition of claim
 10. 13. A method of treating cysticfibrosis in a subject in need of such treatment comprising,administering to said subject a pharmaceutical composition of claim 10.14. A compound represented by Formula VI:

or any racemates, enantiomers, regioisomers, salts, esters, or prodrugsthereof wherein X, Y, L, W, and R_(p) are as defined previously; B isindependently selected from hydrogen, acyl, silane, a substituted orunsubstituted, saturated or unsaturated aliphatic group, a substitutedor unsubstituted, saturated or unsaturated alicyclic group, asubstituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group, or a substituted or unsubstitutedheterocyclic group.
 15. A compound according to claim 14 represented byFormula VII:

where R_(p) as previously defined in claim 1.